Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Written in honor of Dale K. Van Kley, leading specialist on religion and politics in the Old Regime and the French Revolution, these essays examine how Jansenist belief shaped enlightenment ideas, cultural identities, social relations and politics in France throughout the long eighteenth century. Van Kley's work has invited scholars to think beyond the traditional parameters of the Enlightenment and to consider how religious faith functioned in the broader context of Old Regime, Revolutionary, and post-Revolutionary France. In different ways, each (...) essay challenges the idea of an inherent opposition between faith and Enlightenment, which likewise equates modernity with secularization. The authors within this volume address two main questions. Firstly, how did religious belief continue to shape identities and experiences in the long eighteenth century? Secondly, how does this narrative of enduring religious belief in eighteenth-century France help historians rethink the Enlightenment and the French Revolution? The various methodologies used by the contributors illustrate how belief, Enlightenment, and Revolution coexisted and indeed co-mingled in different contexts: politics and political culture, the social and cultural history of ideas, and the history of material culture. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...) autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

Objectives To conduct an independent evaluation of the first phase of the Health Foundation’s Safer Patients Initiative (SPI), and to identify the net additional effect of SPI and any differences in changes in participating and non-participating NHS hospitals. Design Mixed method evaluation involving five substudies, before and after design. Setting NHS hospitals in the United Kingdom. Participants Four hospitals (one in each country in the UK) participating in the first phase of the SPI (SPI1); 18 control hospitals. Intervention The SPI1 (...) was a compound (multi-component) organisational intervention delivered over 18 months that focused on improving the reliability of specific frontline care processes in designated clinical specialties and promoting organisational and cultural change. Results Senior staff members were knowledgeable and enthusiastic about SPI1. There was a small (0.08 points on a 5 point scale) but significant (P<0.01) effect in favour of the SPI1 hospitals in one of 11 dimensions of the staff questionnaire (organisational climate). Qualitative evidence showed only modest penetration of SPI1 at medical ward level. Although SPI1 was designed to engage staff from the bottom up, it did not usually feel like this to those working on the wards, and questions about legitimacy of some aspects of SPI1 were raised. Of the five components to identify patients at risk of deterioration—monitoring of vital signs (14 items); routine tests (three items); evidence based standards specific to certain diseases (three items); prescribing errors (multiple items from the British National Formulary); and medical history taking (11 items)—there was little net difference between control and SPI1 hospitals, except in relation to quality of monitoring of acute medical patients, which improved on average over time across all hospitals. Recording of respiratory rate increased to a greater degree in SPI1 than in control hospitals; in the second six hours after admission recording increased from 40% (93) to 69% (165) in control hospitals and from 37% (141) to 78% (296) in SPI1 hospitals (odds ratio for “difference in difference” 2.1, 99% confidence interval 1.0 to 4.3; P=0.008). Use of a formal scoring system for patients with pneumonia also increased over time (from 2% (102) to 23% (111) in control hospitals and from 2% (170) to 9% (189) in SPI1 hospitals), which favoured controls and was not significant (0.3, 0.02 to 3.4; P=0.173). There were no improvements in the proportion of prescription errors and no effects that could be attributed to SPI1 in non-targeted generic areas (such as enhanced safety culture). On some measures, the lack of effect could be because compliance was already high at baseline (such as use of steroids in over 85% of cases where indicated), but even when there was more room for improvement (such as in quality of medical history taking), there was no significant additional net effect of SPI1. There were no changes over time or between control and SPI1 hospitals in errors or rates of adverse events in patients in medical wards. Mortality increased from 11% (27) to 16% (39) among controls and decreased from 17% (63) to 13% (49) among SPI1 hospitals, but the risk adjusted difference was not significant (0.5, 0.2 to 1.4; P=0.085). Poor care was a contributing factor in four of the 178 deaths identified by review of case notes. The survey of patients showed no significant differences apart from an increase in perception of cleanliness in favour of SPI1 hospitals. Conclusions The introduction of SPI1 was associated with improvements in one of the types of clinical process studied (monitoring of vital signs) and one measure of staff perceptions of organisational climate. There was no additional effect of SPI1 on other targeted issues nor on other measures of generic organisational strengthening. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing the (...) 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. (...) RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype. (shrink)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to Pb (...) had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...) of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during (...) standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

The National Blood Policy in India relies heavily on voluntary blood donors, as they are usually assumed to be associated with low levels of transfusion-transmitted infections . In India, it is mandatory to test every unit of blood collected for hepatitis B, hepatitis C, HIV/AIDS, syphilis and malaria. Donors come to the blood bank with altruistic intentions. If donors test positive to any of the five infections, their blood is discarded. Although the blood policy advocates disclosure of TTI status, donors (...) are not, in practice, informed about their results. The onus is on the donor to contact the blood bank. Out of approximately 16 000 donations in the past 2 years, 438 tested positive for TTI, including 107 for HIV. Only 20% of the donors contacted the blood bank; none of them were HIV positive. Disclosure by blood banks of TTI status by telephone or mail has resulted in serious consequences for some donors. Health providers face an ethical dilemma, in the absence of proper mechanisms in place for disclosure of test results, regarding notification to donors who may test positive but remain ignorant of their TTI status. Given the high cost of neglecting to notify infected donors, the authors strongly recommend the use of rapid tests before collecting blood, instead of the current practice, which takes 3 h to obtain results, and disclosure of results directly to the donor by a counsellor, to avoid dropouts and to ensure confidentiality. (shrink)

This study sought to explore the level of personal wellbeing and identified the determinants of happiness among Indian adolescents and youth. Data were collected from a sample of 495 participants residing in the National Capital Region of Delhi, using the bilingual version of the Personal Wellbeing Index. Their PWI score was 80.06, indicating high happiness levels in the nonwestern normative PWI range. Domains of personal relationships, community connectedness, and safety represented high overall wellbeing with the highest mean scores. Multivariate analysis (...) showed that the least happy group on life as a whole domain was students aged 19–23 years as compared with the 11–14 and 15–18 years age group. Furthermore, men had higher happiness levels on personal safety, while women had higher scores on life achievement. The qualitative analysis illustrated the socio-cultural basis of these wellbeing determinants as rooted in the hierarchical social structures and collectivistic cultural orientation. (shrink)

The development of action representation during adolescence was investigated using a visually guided pointing motor task to test motor imagery. Forty adolescents and 33 adults were instructed to both execute and imagine hand movements from a starting point to a target of varying size. Reaction time was measured for both Execution and Imagery conditions. There is typically a close association between time taken to execute and image actions in adults because action execution and action simulation rely on overlapping neural circuitry. (...) Further, representations of actions are governed by the same speed-accuracy trade-off as real actions, as expressed by Fitts’ Law. In the current study, performance on the VGPT in both adolescents and adults conformed to Fitts’ Law in E and I conditions. However, the strength of association between E and I significantly increased with age, reflecting a refinement in action representation between adolescence and adulthood. (shrink)

Linguists have realised for some time that predicates of the 'know' and 'wonder' classes behave differently in semantic terms with respect to their interrogative complements, but have not so far fully understood how or why. This book seeks to explore and to provide solutions to this and to related problems in explaining the meaning and grammar of embedded interrogatives and the predicates that take interrogative complements.

Mitos ve Logos kavramları Antik Yunan uygarlığında söz kavramına karşılık gelen sözcükleri karşılamak için kullanılmıştır. Felsefe tarihinin başlangıcı için yapılan tanımlamalarda ise mitos kavramının yerine logos kavramının tercih edilmesi iki kavram arasında bir farklılığı ortaya koymak için yapılmaktadır. Bu ayrımın nedeni ise mitos’un daha çok dinsel içerikle anılması logos’un ise içerisinde bir tür akılsallık barındırması şeklindeki yorumlarda kendini göstermektedir. Ancak söz konusu ayrımın ilk doğa filozofu/ilk felsefeci olarak nitelendirilen Thales için geçerli olup olmadığı geçmişte olduğu gibi günümüzde de halen tartışılmaktadır. (...) Felsefe tarihi yazımlarında ilk sıraya konan Thales’in anılan kavramları gerçekten farklı şekilde yorumlayıp yorumlamadığı bizce de tartışmaya açık bir husustur. Bu açıdan bakıldığında Thales, söz konusu kavramları iki farklı problemler alanı olarak mı görmüştür? Onun düşüncelerinde kendinden önceki mitolojik mirasın izleri bulunabilir mi? O, katışıksız bir rasyonel midir, yoksa henüz felsefenin yeni filizlendiği bir toplumda bir ara basamağı mı temsil etmektedir? Bu makalenin içerisinde tartışacağımız bu sorular, felsefe tarihinin başlangıcına ilişkin kavramsal arka planın ne olduğu hakkında bize katkı sağlayacaktır. (shrink)

“Doğal din” terimi, bazen doğanın kendisinin ilahi olduğu bir panteistik doktrine atıfta bulunur. “Doğal teoloji” terimi ise aksine, başlangıçta gözlemlenen doğal gerçekler temelinde (ve bazen) Tanrı’nın varlığını savunmaya yönelik projeye atıfta bulunur. Bununla birlikte çağdaş felsefede, hem “doğal din” hem de “doğal teoloji” genel olarak, dinî veya teolojik konuları araştırmak için insana, “doğal” olan bilişsel yetilerini – akıl, algı, içgözlem- kullanma projesini ifade eder. Doğal din veya teoloji, mevcut anlayış üzerine, doğayla ilgili ampirik araştırmalarla sınırlı olmamakla birlikte ayrıca panteistik bir (...) sonuçla da bağlantılı değildir. Bununla birlikte o, özel doğal olmayan yetilere (ESP, telepati, mistik deneyim) veya doğaüstü bilgi kaynaklarına (kutsal metinler, vahiy teolojisi, inanç otoriteleri, doğrudan doğaüstü iletişim) hitap etmekten kaçınır. Genel olarak, doğal din veya teoloji (bundan böyle “doğal teoloji” olarak anılacaktır), diğer felsefi ve bilimsel girişimlerle aynı rasyonel inceleme standartlarına uymayı amaçlamaktadır ve aynı değerlendirme ve eleştiri yöntemlerine tabidir. (shrink)

This paper presents an analysis of negative polarity items (NPIs) in Hindi. It is noted that NPIs in this language are composed of a (weak) indefinite plus a particle bhii meaning ‘even’. It is argued that the compositional semantics of this combination explains their behavior as NPIs as well as their behavior as free choice (FC) items. I assume that weak Hindi indefinites like ek and koi are to be viewed as a predicate that I call one, a predicate that (...) is true of everything that exists. I further assume that bhii exhibits association with focus with the indefinite, and that this leads to contradictory implicatures in positive contexts. The behavior of these phrases in a variety of syntactic contexts is discussed, including constructions like correlatives. Finally, I provide a comparison with analyses of English any, and discuss the relevance of the analysis presented here for that of any. (shrink)

Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher‐order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC‐binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. This (...) review aims to describe the current understanding of the dynamic nature of the cohesin‐DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin‐centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling. (shrink)

Modal ontolojik argüman, Tanrı’nın varlığını sadece bilfiil gerçek olan bu dünyada değil, bütün mümkün dünyalarda göstermeye yönelik bir argümandır. Anselm’in (1033-1109) Proslogion adlı eserinin 3. bölümünde “kendisinden daha büyüğü düşünülemeyen” şeklinde tanımlanan; Tanrı’nın var olmamasının da düşünülemeyeceğini, bu yüzden de varolmamasının imkansızlığı üzerinde kurulu yeni bir argüman bulunduğunu öne süren bazı araştırmacılar, bu argümanı mümkün dünyalar semantiği yardımıyla formüle edip, “modal ontolojik argüman” şeklinde adlandırmışlardır. Çok farklı şekillerde formüle edilmiş bu argüman kabaca Tanrı’nın mümkünse zorunlu olması, dolayısıyla bilfiil gerçek olan (...) bu dünyada da var olması gerektiğini savunur. (shrink)

Studies of epistemic communities and collaborative research in the social sciences have deepened the understanding of how science works, and more specifically how the social dimensions of scientific practice both enable and impede social scientists in realizing their epistemic goals. Two types of studies of epistemic communities are distinguished: general theories of epistemic communities aim to construct accounts of theoretical change applicable to all social scientific specialties, whereas historical studies emphasize the contingencies that affect specific social scientific disciplines, subfields, or (...) institutions. Although collaborative research plays a less pronounced role in the social sciences than in the natural sciences, collaboration has enabled social scientists to investigate topics that would otherwise be difficult to investigate. (shrink)

Çağdaş epistemoloji içerisinde, dışsalcı, güvenilirci ve erdeme dayalı epistemolojik tartışmaların bir benzerini, dini epistemoloji içerisinde etkili bir şekilde yer edinen ve reformcu epistemoloji olarak bilinen yaklaşım üzerinden görebilmek mümkündür. Alvin Plantinga, Nicholas Wolterstorff ve William Alston gibi filozofların öne çıktığı bu yaklaşımın ana iddiası, kanıta ya da argümana dayanmaksızın, Tanrı’nın varlığına inanmanın bütünüyle doğru, rasyonel, makul ve güvenilir olacağı şeklindeki bir tezdir. Kanıtın, gerekçelendirme için zorunlu bir koşul olmadığı fikri, algısal deneyimlerin gerekçelendirilmesine benzer şekilde, dini deneyimlerin de öyle olduğu ve (...) dolayısıyla, aynı epistemik statüye sahip olması gerektiğini öne süren, eşitlik tezine dayanır. İlk ortaya çıktığı günden bugüne, üzerinde çokça konuşulan ve tartışılan bir yaklaşım olan reformcu epistemoloji, özellikle son beş yıl içerisinde, oldukça farklı bir hale gelmiştir. Zira bu yaklaşımı, kanıtsalcılıkla uyumlu, erdem epistemolojisiyle bağlantılı ve diğer teistik dinler üzerinden değerlendiren yeni çalışmalar ortaya çıkmıştır. Bu nedenle, bu makalede, reformcu epistemoloji ana hatlarıyla ele alınmıştır. Beraberinde, ona yöneltilen itirazlara değinilmiş ve sonrasında, bahsi geçen yenilik iddiaları soruşturulmaya çalışılmıştır. Son olarak, teistik inancın rasyonalitesiyle ilgili, farklı bir bakış açısı sunulmuştur. (shrink)

We introduce the notion of complexity, first at an intuitive level and then in relatively more concrete terms, explaining the various characteristic features of complex systems with examples. There exists a vast literature on complexity, and our exposition is intended to be an elementary introduction, meant for a broad audience. -/- Briefly, a complex system is one whose description involves a hierarchy of levels, where each level is made of a large number of components interacting among themselves. The time evolution (...) of such a system is of a complex nature, depending on the interactions among subsystems in the next level below the one under consideration and, at the same time, conditioned by the level above, where the latter sets the context for the evolution. Generally speaking, the interactions among the constituents of the various levels lead to a dynamics characterized by numerous characteristic scales, each level having its own set of scales. What is more, a level commonly exhibits ‘emergent properties’ that cannot be derived from considerations relating to its component systems taken in isolation or to those in a different contextual setting. In the dynamic evolution of some particular level, there occurs a self-organized emergence of a higher level and the process is repeated at still higher levels. -/- The interaction and self-organization of the components of a complex system follow the principle commonly expressed by saying that the ‘whole is different from the sum of the parts’. In the case of systems whose behavior can be expressed mathematically in terms of differential equations this means that the interactions are nonlinear in nature. -/- While all of the above features are not universally exhibited by complex systems, these are nevertheless indicative of a broad commonness relative to which individual systems can be described and analyzed. There exist measures of complexity which, once again, are not of universal applicability, being more heuristic than exact. The present state of knowledge and understanding of complex systems is itself an emerging one. Still, a large number of results on various systems can be related to their complex character, making complexity an immensely fertile concept in the study of natural, biological, and social phenomena. -/- All this puts a very definite limitation on the complete description of a complex system as a whole since such a system can be precisely described only contextually, relative to some particular level, where emergent properties rule out an exact description of more than one levels within a common framework. -/- We discuss the implications of these observations in the context of our conception of the so-called noumenal reality that has a mind-independent existence and is perceived by us in the form of the phenomenal reality. The latter is derived from the former by means of our perceptions and interpretations, and our efforts at sorting out and making sense of the bewildering complexity of reality takes the form of incessant processes of inference that lead to theories. Strictly speaking, theories apply to models that are constructed as idealized versions of parts of reality, within which inferences and abstractions can be carried out meaningfully, enabling us to construct the theories. -/- There exists a correspondence between the phenomenal and the noumenal realities in terms of events and their correlations, where these are experienced as the complex behavior of systems or entities of various descriptions. The infinite diversity of behavior of systems in the phenomenal world are explained within specified contexts by theories. The latter are constructs generated in our ceaseless attempts at interpreting the world, and the question arises as to whether these are reflections of `laws of nature' residing in the noumenal world. This is a fundamental concern of scientific realism, within the fold of which there exists a trend towards the assumption that theories express truths about the noumenal reality. We examine this assumption (referred to as a ‘point of view’ in the present essay) closely and indicate that an alternative point of view is also consistent within the broad framework of scientific realism. This is the view that theories are domain-specific and contextual, and that these are arrived at by independent processes of inference and abstractions in the various domains of experience. Theories in contiguous domains of experience dovetail and interpenetrate with one another, and bear the responsibility of correctly explaining our observations within these domains. -/- With accumulating experience, theories get revised and the network of our theories of the world acquires a complex structure, exhibiting a complex evolution. There exists a tendency within the fold of scientific realism of interpreting this complex evolution in rather simple terms, where one assumes (this, again, is a point of view) that theories tend more and more closely to truths about Nature and, what is more, progress towards an all-embracing ‘ultimate theory’ -- a foundational one in respect of all our inquiries into nature. We examine this point of view closely and outline the alternative view -- one broadly consistent with scientific realism -- that there is no ‘ultimate’ law of nature, that theories do not correspond to truths inherent in reality, and that successive revisions in theory do not lead monotonically to some ultimate truth. Instead, the theories generated in succession are incommensurate with each other, testifying to the fact that a theory gives us a perspective view of some part of reality, arrived at contextually. Instead of resembling a monotonically converging series successive theories are analogous to asymptotic series. -/- Before we summarize all the above considerations, we briefly address the issue of the complexity of the {\it human mind} -- one as pervasive as the complexity of Nature at large. The complexity of the mind is related to the complexity of the underlying neuronal organization in the brain, which operates within a larger biological context, its activities being modulated by other physiological systems, notably the one involving a host of chemical messengers. The mind, with no materiality of its own, is nevertheless emergent from the activity of interacting neuronal assemblies in the brain. As in the case of reality at large, there can be no ultimate theory of the mind, from which one can explain and predict the entire spectrum of human behavior, which is an infinitely rich and diverse one. (shrink)